Brain edema is an accumulation of water within the brain tissue. It is a frequent complication after brain damage (stroke or injury)31. Edema tends to be maximal at approximately 2 days after injury, and can persist as long as one week. Edema causes the brain to swell, and when the brain swells, pressure inside the head rises and causes further permanent damage or potentially leads to death. Intravenous administration of drugs (e.g. mannitol or other osmotic agents) can dehydrate the uninjured parts of brain to temporarily relieve pressure. Unfortunately, this approach is limited because the osmotic agents enter damaged brain through leaking blood vessels and the swelling in these regions becomes worse (“rebound” phenomenon)25. In desperation, surgeons can remove the skull that overlies the damaged brain to allow the brain to swell outward21. Experimentally, cooling the brain from the normal 37° C. to ˜32° C. can be protective, but clinically local cooling of damaged brain is difficult and cooling of the entire body can have serious side effects (e.g. infection, bleeding). Therefore, there is no effective clinical treatment for severe cases of brain edema.
Interstitial fluid (ISF), also referred to as extracellular fluid, moves through brain by diffusion among cells and by bulk flow especially alongside blood vessels1. The predominant flow is toward the ventricular cavities in the center of the brain, where it contributes to cerebrospinal fluid (CSF) formation. The pia mater/glia limitans on the outer surface of the brain may act as a physical barrier and regulatory interface between the extracellular compartment of the brain and the CSF in the subarachnoid space, which surrounds the brain11. The arachnoid is a thin tissue layer that contains the CSF around the brain and serves as a barrier against the bulk movement of fluids and large molecular weight substances2. The arachnoid is in intimate contact with, but not attached to, the dura mater, which is a tough fibrous layer that is adherent to the inner surface of the skull. Electrophysiological and tracer studies show that exchange of small molecules can occur across the pia, arachnoid, and even the thin dura of small animals3,29,30,35,43,54.
As discussed above, brain edema is an accumulation of water within the brain parenchyma. It is a universal physiological reaction to brain damage. The localization of edema fluid depends on the etiology of brain damage, and is defined by accumulation in extracellular (“vasogenic”; i.e. due to leaking blood vessels) or intracellular (also called “cytotoxic”; i.e. due to cell swelling when function of the cell membrane fails from exposure to disturbed environment or when energy supplies such as oxygen and glucose are lacking) compartments, potentially in combination. Water and fluid retention can be aggravated by the presence of small molecules that leak through damaged blood vessels and from damaged cells into the extracellular space. Here they can act as osmotic agents that prevent the free flow of water. Edema contributes to brain swelling and elevated intracranial pressure (ICP)27,51. As discussed above, there remains no effective clinical treatment for severe cases37, despite availability of hyperosmolar agents5,53, barbiturates42, physiologic support38, external ventricular drainage, and hemicraniectomy32,44.
Physical processes such as osmosis and diffusion facilitate the transport of water and dissolved small molecules from solutions through membranes. Dialysis is defined as the process of separating crystalloids (ions and other small molecules dissolved in a liquid) and colloids (large molecules, e.g. proteins, dissolved or suspended in a liquid) in solution by the difference in their rates of diffusion across a semipermeable membrane. This principle is in use for therapeutic hemodialysis (i.e. cleansing of the blood in the case of kidney failure)15 and extracellular fluid sampling by intraparenchymal brain microdialysis (wherein a small semipermeable catheter filled with a hyperosmotic solution is introduced into the tissue; water and small molecules are drawn into the catheter)20. In experimental studies on injured rat brain, edema was reduced when negative hydrostatic pressure was applied for 24 hours to ultra-thin small diameter cuprophan tubes implanted into injury site48,49.